Ebook Pharmacology for anaesthesia and intensive care (4th edition): Part 2

SECTION III Cardiovascular drugs

13

Sympathomimetics

Physiology
Autonomic nervous system
he autonomic nervous system (ANS) is a complex system of neurones that controls the
body’s internal milieu. It is not under voluntary control and is anatomically distinct from
the somatic nervous system. Its eferent limb controls individual organs and smooth
muscle, while its aferent limb relays information (occasionally in somatic nerves) concerning visceral sensation and may result in relex arcs.
he hypothalamus is the central point of integration of the ANS, but is itself under
the control of the neocortex. However, not all autonomic activity involves the hypothalamus: locally, the gut coordinates its secretions; some relex activity is processed within
the spinal cord; and the control of vital functions by baroreceptors is processed within
the medulla. he ANS is divided into the parasympathetic and sympathetic nervous
systems.

Parasympathetic nervous system
he parasympathetic nervous system (PNS) is made up of pre- and post-ganglionic ibres.
he pre-ganglionic ibres arise from two locations (Figure 13.1):
• Cranial nerves (III, VII, IX, X) – which supply the eye, salivary glands, heart, bronchi,
upper gastrointestinal tract (to the splenic lexure) and ureters
• Sacral ibres (S2, 3, 4) – which supply distal bowel, bladder and genitals.
All these ibres synapse within ganglia that are close to, or within, the efector
organ. he post-ganglionic neurone releases acetylcholine, which acts via nicotinic
receptors.
he PNS may be modulated by anticholinergics (see Chapter 19) and anticholinesterases (see Chapter 12).

Sympathetic nervous system
he sympathetic nervous system (SNS) is also made up of pre- and post-ganglionic ibres.

he pre-ganglionic ibres arise within the lateral horns of the spinal cord at the thoracic
and upper lumbar levels (T1–L2) and pass into the anterior primary rami, and via the
white rami communicans into the sympathetic chain or ganglia where they may either
synapse at that or an adjacent level, or pass anteriorly through a splanchnic nerve to

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Section III: Cardiovascular drugs
SNS

Circular muscles of iris
VII

Lacrimal glands

Radial muscle of iris

IX
Cervical

Salivary glands

III

Brainstem

PNS

Salivary glands
Blood vessels

X (vagus)

Heart, Lungs, Blood vessels

Coeliac ganglion

Thoracic

Heart
Lungs
Gut

Gut and Kidney

Sup'

Inf' Mesenteric ganglion

Descending colon, Bladder,
Genitals

Sacral

Lumbar

Kidney
Ureter
Bladder
Descending colon
Genitals
S 2,3,4

Figure 13.1 Simplified diagram of the autonomic nervous system.

Table 13.1 Summary of transmitters within the autonomic nervous system.

PNS
SNS
Adrenal medulla
Sweat glands

Pre-ganglionic

Post-ganglionic

acetylcholine
acetylcholine
acetylcholine
acetylcholine

acetylcholine
noradrenaline
–
acetylcholine

synapse in a prevertebral ganglion (Figure 13.2). he unmyelinated post-ganglionic ibres
then pass into the adjacent spinal nerve via the grey rami communicans. hey release
noradrenaline, which acts via adrenoceptors.
he adrenal medulla receives presynaptic ibres that synapse directly with its chromafin cells using acetylcholine as the transmitter. It releases adrenaline into the circulation,
which, therefore, acts as a hormone, not a transmitter.
Post-ganglionic sympathetic ibres release acetylcholine to innervate sweat glands.
All pre-ganglionic ANS ibres are myelinated and release acetylcholine, which acts via
nicotinic receptors (Table 13.1).

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13: Sympathomimetics

Spinal cord

DRG

GRC

WRC
APR

SC
PVG

Figure 13.2 Various connections of the sympathetic nervous system. DRG, dorsal root

ganglion; APR, anterior primary rami; WRC, white rami communicans; GRC, grey rami
communicans; PVG, prevertebral ganglion; SC, sympathetic chain.

Sympathomimetics
Sympathomimetics exert their efects via adrenoceptors or dopamine receptors either
directly or indirectly. Direct-acting sympathomimetics attach to and act directly via
these receptors, while indirect-acting sympathomimetics cause the release of noradrenaline to produce their efects via these receptors.
he structure of sympathomimetics is based on a benzene ring with various amine
side chains attached at the C1 position. Where a hydroxyl group is present at the C3 and
C4 positions the agent is known as a catecholamine (because 3,4-dihydroxybenzene is
otherwise known as ‘catechol’).
Sympathomimetic and other inotropic agents will be discussed under the following
headings:
• Naturally occurring catecholamines
• Synthetic agents
• Other inotropic agents

Naturally occurring catecholamines
Adrenaline, noradrenaline and dopamine are the naturally occurring catecholamines
and their synthesis is interrelated (Figure 13.3). hey act via adrenergic and dopaminergic receptors, which are summarized in Table 13.2.
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Section III: Cardiovascular drugs
Phenylalanine

H

CH2

C

NH2

COOH
Phenylalanine hydroxylase (mainly in liver)
Cytoplasm
Tyrosine

H
CH2

C

Actively concentrated in adrenergic
neurones and adrenal medulla
NH2

COOH
HO
Tyrosine hydroxylase (rate limiting step)
Dihydroxyphenylalanine
(DOPA)
HO

H
CH2

C

NH2

COOH
HO
Dopa decarboxylase
Dopamine
HO
CH2

CH2

NH2

HO
Granulated vesicles

Dopamine β-hydroxylase

Noradrenaline
HO

H
C

HO
Only within adrenal medulla

CH2

NH2

OH

Phenylethanolamine-N-methyltransferase (PNMT)

Adrenaline
HO

H
C

HO

OH

H
CH2

N
CH3

Figure 13.3 Catecholamine synthesis.

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13: Sympathomimetics
Table 13.2 Actions and mechanisms of adrenoceptors.
Actions when
stimulated

Receptor

Subtype

Location

α

1

vascular smooth
muscle

vasoconstriction

2

widespread
throughout the
nervous system

1

platelets

sedation, analgesia,
attenuation of
sympathetically
mediated
responses
platelet
aggregation
+ ve inotropic and
chronotropic
efect
relaxation of
smooth muscle

β

heart

D

2

bronchi, vascular
smooth muscle,
uterus (and heart)

3

adipose tissue

lipolysis

1

within the central
nervous system

modulates
extrapyramidal
activity
vasodilatation
of renal and
mesenteric
vasculature
reduced pituitary
hormone output
inhibit further
noradrenaline
release

peripherally

2

within the central
nervous system
peripherally

Mechanism

Gq-coupled
phospholipase C
activated →↑ IP3 →↑
Ca2+
Gi-coupled adenylate
cyclase inhibited →↓
cAMP

Gs-coupled adenylate
cyclase activated →↑
cAMP
Gs-coupled adenylate
cyclase activated →↑
cAMP →↑ Na+/K+
ATPase activity and
hyperpolarization
Gs-coupled adenylate
cyclase activated →↑
cAMP
Gs-coupled adenylate
cyclase activated →↑
cAMP

Gi-coupled adenylate
cyclase inhibited →↓
cAMP

Adrenaline
Presentation and uses
Adrenaline is presented as a clear solution containing 0.1–1 mg/ml for administration as

a bolus in asystole or anaphylaxis or by infusion (dose range 0.01–0.5 µg/kg/min) in the
critically ill with circulatory failure. It may also be nebulized into the upper airway where

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Section III: Cardiovascular drugs
its vasoconstrictor properties will temporarily reduce the swelling associated with acute
upper airway obstruction. A 1% ophthalmic solution is used in open-angle glaucoma,
and a metered dose inhaler delivering 280 µg for treatment of anaphylaxis associated
with insect stings or drugs. In addition, it is presented in combination with local anaesthetic solutions at a strength of 1 in 80 000–200 000.

Mechanism of action
Adrenaline exerts its efects via α- and β-adrenoceptors. α1-Adrenoceptor activation stimulates phospholipase C (via Gq), which hydrolyses phosphatidylinositol bisphosphate
(PIP2). Inositol triphosphate (IP3) is released, which leads to increased Ca2+ availability
within the cell. α2-Adrenoceptor activation is coupled to Gi-proteins that inhibit adenylate cyclase and reduce cAMP concentration. β-Adrenoceptors are coupled to Gs-proteins
that activate adenylate cyclase, leading to an increase in cAMP and speciic phosphorylation depending on the site of the adrenoceptor.

Effects
• Cardiovascular – the efects of adrenaline vary according to dose. When administered
as a low-dose infusion, β efects predominate. his produces an increase in cardiac
output, myocardial oxygen consumption, coronary artery dilatation and reduces the
threshold for arrhythmias. Peripheral β efects may result in a fall in diastolic blood
pressure and peripheral vascular resistance. At high doses by infusion or when given
as a 1 mg bolus during cardiac arrest, α1 efects predominate causing a rise in systemic
vascular resistance. It is often used in combination with local anaesthetics to produce vasoconstriction before dissection during surgery. When used with halothane,
the dose should be restricted to 100 µg per 10 minutes to avoid arrhythmias. It should

not be iniltrated into areas supplied by end arteries lest their vascular supply become
compromised. Extravasation can cause tissue necrosis.
• Respiratory – adrenaline produces a small increase in minute volume. It has potent
bronchodilator efects although secretions may become more tenacious. Pulmonary
vascular resistance is increased.
• Metabolic – adrenaline increases the basal metabolic rate. It raises plasma glucose by
stimulating glycogenolysis (in liver and skeletal muscle), lipolysis and gluconeogenesis.
Initially insulin secretion is increased (a β2 efect) but is often overridden by an α efect,
which inhibits its release and compounds the increased glucose production. Glucagon
secretion and plasma lactate are also raised. Lipase activity is augmented resulting in
increased free fatty acids, which leads to increased fatty acid oxidation in the liver and
ketogenesis. hese metabolic efects limit its use, especially in those with diabetes. Na+
reabsorption is increased by direct stimulation of tubular Na+ transport and by stimulating renin and, therefore, aldosterone production. β2-Receptors are responsible for
the increased transport of K+ into cells, which follows an initial temporary rise as K+ is
released from the liver.

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13: Sympathomimetics
• Central nervous system – it increases MAC and increases the peripheral pain
threshold.
• Renal – renal blood low is moderately decreased and the increase in bladder sphincter
tone may result in diiculty in micturition.

Kinetics
Adrenaline is not given orally due to inactivation. Subcutaneous absorption is less rapid

than intramuscular. Tracheal absorption is erratic but may be used in emergencies where
intravenous access is not available.
Adrenaline is metabolized by mitochondrial MAO and catechol O-methyl transferase
(COMT) within the liver, kidney and blood to the inactive 3-methoxy-4-hydroxymandelic
acid (vanillylmandelic acid or VMA) and metadrenaline, which is conjugated with glucuronic acid or sulfates, both of which are excreted in the urine. It has a short half-life
(about 2 minutes) due to rapid metabolism.

Noradrenaline
Presentation and uses
Noradrenaline is presented as a clear solution containing 0.2–2 mg/ml noradrenaline
acid tartrate, which is equivalent to 0.1–1 mg/ml of noradrenaline base, and contains
the preservative sodium metabisulite. It is used as an intravenous infusion (dose range
0.05–0.5 µg/kg/min) to increase the systemic vascular resistance.

Mechanism of action
Its actions are mediated mainly via stimulation of α1-adrenoceptors but also
β-adrenoceptors.

Effects
• Cardiovascular – the efects of systemically infused noradrenaline are slightly diferent from those of endogenous noradrenaline. Systemically infused noradrenaline
causes peripheral vasoconstriction, increases systolic and diastolic blood pressure and
may cause a relex bradycardia. Cardiac output may fall and myocardial oxygen consumption is increased. A vasodilated coronary circulation carries an increased coronary blood low. Pulmonary vascular resistance may be increased and venous return is
increased by venoconstriction. In excess it produces hypertension, bradycardia, headache and excessive peripheral vasoconstriction, occasionally leading to ischaemia
and gangrene of extremities. Extravasation can cause tissue necrosis. Endogenously
released noradrenaline causes tachycardia and a rise in cardiac output.
• Splanchnic – renal and hepatic blood low falls due to vasoconstriction.
• Uterus – blood low to the pregnant uterus is reduced and may result in fetal bradycardia. It may also exert a contractile efect and cause fetal asphyxia.

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Section III: Cardiovascular drugs
• Interactions – despite being a direct-acting sympathomimetic amine, noradrenaline
should be used with caution in patients taking monoamine oxidase inhibitors (MAOIs)
as its efects may be exaggerated and prolonged.

Kinetics
For endogenously released noradrenaline, Uptake 1 describes its active uptake back
into the nerve terminal where it is metabolized by MAO (COMT is not present in sympathetic nerves) or recycled. It forms the main mechanism by which noradrenaline is
inactivated. Uptake 2 describes the difusion away from the nerve and is less important.
Noradrenaline reaches the circulation in this way and is metabolized by COMT to the
inactive VMA and normetadrenaline, which is conjugated with glucuronic acid or sulfates, both of which are excreted in the urine. It has a short half-life (about 2 minutes) due
to rapid metabolism. Unlike adrenaline and dopamine, up to 25% is taken up as it passes
through the lungs.

Dopamine
In certain cells within the brain and interneurones of the autonomic ganglia, dopamine is
not converted to noradrenaline and is released as a neurotransmitter.

Presentation and uses
Dopamine is presented as a clear solution containing 200 or 800 mg in 5 ml water with
sodium metabisulite. It is used to improve haemodynamic parameters and urine
output.

Mechanism of action
In addition to its efects on α and β adrenoceptors, dopamine also acts via dopamine
(D1 and D2) receptors via Gs and Gi coupled adenylate cyclase leading to increased or

decreased levels of cAMP.

Effects
• Cardiovascular – these depend on its rate of infusion and vary between patients. At
lower rates (up to 10 µg/kg/min) β1 efects predominate leading to increased contractility, heart rate, cardiac output and coronary blood low. In addition to its direct efects,
it also stimulates the release of endogenous noradrenaline. At higher rates (>10 µg/kg/
min) α efects tend to predominate leading to increased systemic vascular resistance
and venous return. In keeping with other inotropes an adequate preload is essential to
help control tachycardia. It is less arrhythmogenic than adrenaline. Extravasation can
cause tissue necrosis.
• Respiratory – infusions of dopamine attenuate the response of the carotid body to hypoxaemia. Pulmonary vascular resistance is increased.

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13: Sympathomimetics
• Splanchnic – dopamine has been shown to vasodilate mesenteric vessels via D1
receptors. However, the improvement in urine output may be entirely due to inhibition of proximal tubule Na+ reabsorption and an improved cardiac output and blood
pressure.
• Central nervous system – dopamine modulates extrapyramidal movement and inhibits
the secretion of prolactin from the pituitary gland. It cannot cross the blood–brain barrier, although its precursor, L -dopa, can.
• Miscellaneous – owing to stimulation of the chemoreceptor trigger zone it causes nausea and vomiting. Gastric transit time is also increased.
• Interactions – despite being a direct-acting sympathomimetic amine the efects of
dopamine may be signiicantly exaggerated and prolonged during MAOI therapy.

Kinetics
Dopamine is only administered intravenously and preferably via a central vein. It acts

within 5 minutes and has a duration of 10 minutes. Metabolism is via MAO and COMT
in the liver, kidneys and plasma to inactive compounds (3,4-dihydroxyphenylacetic acid
and homovanillic acid; HVA) which are excreted in the urine as sulfate and glucuronide
conjugates. About 25% of an administered dose is converted to noradrenaline in sympathetic nerve terminals. Its half-life is about 3 minutes.

Synthetic agents
Of the synthetic agents, only isoprenaline, dobutamine and dopexamine are classiied
as catecholamines as only they contain hydroxyl groups on the 3- and 4- positions of the
benzene ring (Figure 13.4).

α1-Agonists
Phenylephrine
Phenylephrine is a direct-acting sympathomimetic amine with potent α1-agonist actions.
It causes a rapid rise in systemic vascular resistance and blood pressure. It has no efect
on β-adrenoceptors.

Presentation and uses
Phenylephrine is presented as a clear solution containing 10 mg in 1 ml. Bolus doses of
50–100 µg are used intravenously although 2–5 mg may be administered intramuscularly
or subcutaneously for a more prolonged duration. It is used to increase a low systemic
vascular resistance associated with spinal anaesthesia or systemically administered
drugs. In certain patients, general anaesthesia may drop the systemic vascular resistance
and reverse a left-to-right intracardiac shunt; this may be reversed by phenylephrine. It is
also available for use as a nasal decongestant and mydriatic agent. It may have a limited
use in the treatment of supraventricular tachycardia associated with hypotension.

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Section III: Cardiovascular drugs
Phenylephrine
HO

H
C

H
CH2

N
CH3

OH

Isoprenaline

H

H
CH2

C

HO

H

N
C

OH

CH3

CH3
HO

Dobutamine

H
C

HO

CH2

H

H

N

C

OH

(CH2)2

OH

CH3

HO

Dopexamine

H

H
(CH2)2

HO

N

(CH2)6

(CH2)2

N

HO

Ephedrine

Metaraminol
HO

H

H

C

C

H

H

H

C

C

N

OH

CH3

CH3

Salbutamol
H
NH2

HO

(CH2)2

N
C(CH3)3

OH CH3
HO H2C

Figure 13.4 Structure of some synthetic sympathomimetic amines.

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13: Sympathomimetics

Effects
• Cardiovascular – phenylephrine raises the systemic vascular resistance and blood
pressure and may result in a relex bradycardia, all of which results in a drop in cardiac
output. It is not arrhythmogenic.
• Central nervous system – it has no stimulatory efects.
• Renal – blood low falls in a manner similar to that demonstrated by noradrenaline.
• Uterus – while its use in obstetrics results in a more favourable cord gas proile it has not
yet gained widespread acceptance due to the possibility of accidental overdose.

Kinetics
Intravenous administration results in a rapid rise in blood pressure, which lasts 5–10
minutes, while intramuscular or subcutaneous injection takes 15 minutes to work but
lasts up to 1 hour. It is metabolized in the liver by MAO. he products of metabolism and
their route of elimination have not been identiied.

β-Agonists
Isoprenaline
Isoprenaline is a highly potent synthetic catecholamine with actions at β1- and β2adrenoceptors. It has no α efects.

Presentation and uses
Isoprenaline is presented as a clear solution containing 1 mg/ml for intravenous infusion and as a metered dose inhaler delivering 80 or 400 µg. It is no longer used to treat
reversible airway obstruction as this was associated with an increased mortality. More
speciic β2-agonists are now used (e.g. salbutamol). he 30 mg tablets are very rarely used.
It is used intravenously to treat severe bradycardia associated with atrioventricular (AV)
block or β-blockers (dose range 0.5–10 µg/min).

Effects
• Cardiovascular – stimulation of β1-adrenoceptors increases heart rate, myocardial contractility, automaticity and cardiac output. he efects on blood pressure are varied.
he β2 efects may drop the systemic vascular resistance so that the increase in cardiac output is insuicient to maintain blood pressure. Myocardial oxygen delivery may
decrease signiicantly when tachycardia reduces diastolic coronary illing time and the
reduced diastolic blood pressure reduces coronary perfusion. Some coronary vasodilatation occurs to attenuate this.
• Respiratory – isoprenaline is a potent bronchodilator and inhibits histamine release in
the lungs, improving mucous low. Anatomical dead space and ventilation perfusion
mismatching increases which may lead to systemic hypoxaemia.
• Central nervous system – isoprenaline has stimulant efects on the CNS.

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Section III: Cardiovascular drugs
• Splanchnic – mesenteric and renal blood low is increased.
• Metabolic – its β efects lead to a raised blood glucose and free fatty acids.

Kinetics
When administered orally it is well absorbed but extensive irst-pass metabolism results
in a low oral bioavailability, being rapidly metabolized by COMT within the liver. A signiicant fraction is excreted unchanged in the urine along with conjugated metabolites.

Dobutamine
Dobutamine is a direct-acting synthetic catecholamine derivative of isoprenaline. β1
efects predominate but it retains a small efect at β2-adrenoceptors.

Presentation and uses
Dobutamine is presented in 20 ml water containing 250 mg dobutamine and sodium
metabisulite or in 5 ml water containing 250 mg dobutamine and ascorbic acid. It is
used to augment low cardiac output states associated with myocardial infarction, cardiac
surgery and cardiogenic shock (dose range 0.5–20 µg/kg/min). It is also used in cardiac
stress testing as an alternative to exercise.

Effects
• Cardiovascular – its main actions are direct stimulation of β1-receptors resulting in
increased contractility, heart rate and myocardial oxygen requirement. he blood
pressure is usually increased despite a limited fall in systemic vascular resistance
via β2 stimulation. It may precipitate arrhythmias including an increased ventricular
response rate in patients with atrial ibrillation or lutter, due to increased AV conduction. It should be avoided in patients with cardiac outlow obstruction (e.g. aortic stenosis, cardiac tamponade).
• Splanchnic – it has no efect on the splanchnic circulation although urine output may
increase following a rise in cardiac output.

Kinetics
Dobutamine is only administered intravenously. It is rapidly metabolized by COMT to
inactive metabolites that are conjugated and excreted in the urine. It has a half-life of 2
minutes.

Dopexamine
Dopexamine is a synthetic analogue of dopamine.

Presentation and uses
Dopexamine is presented as 50 mg in 5 ml (at pH 2.5) for intravenous use. It is used to
improve cardiac output and improve mesenteric perfusion (dose range 0.5–6 µg/kg/min).
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13: Sympathomimetics

Mechanism of action
Dopexamine stimulates β2-adrenoceptors and dopamine (D1) receptors and may
also inhibit the re-uptake of noradrenaline. It has only minimal efect on D2 and β1adrenoceptors, and no efect on α-adrenoceptors.

Effects
• Cardiovascular – while it has positive inotropic efects (due to cardiac β2-receptors),
improvements in cardiac output are aided by a reduced afterload due to peripheral
β2 stimulation, which may reduce the blood pressure. It produces a small increase in
coronary blood low and there is no change in myocardial oxygen extraction. he alterations in heart rate are varied and it only rarely precipitates arrhythmias.
• Mesenteric and renal – blood low to the gut and kidneys increases due to an increased

cardiac output and reduced regional vascular resistance. Urine output increases. It
may cause nausea and vomiting.
• Respiratory – bronchodilation is mediated via β2 stimulation.
• Miscellaneous – tremor and headache have been reported.

Kinetics
Dopexamine is cleared rapidly from the blood and has a half-life of 7 minutes.

Salbutamol
Salbutamol is a synthetic sympathomimetic amine with actions mainly at β2adrenoceptors.

Presentation and uses
Salbutamol is presented as a clear solution containing 50–500 µg/ml for intravenous infusion after dilution, a metered dose inhaler (100 µg) and a dry powder (200–400 µg) for
inhalation, a solution containing 2.5–5 mg/ml for nebulization, and oral preparations
(syrup 0.4 mg/ml and 2, 4 or 8 mg tablets). It is used in the treatment of reversible lower
airway obstruction and occasionally in premature labour.

Effects
• Respiratory – its main efects are relaxation of bronchial smooth muscle. It reverses
hypoxic pulmonary vasoconstriction, increasing shunt, and may lead to hypoxaemia.
Adequate oxygen should, therefore, be administered with nebulized salbutamol.
• Cardiovascular – the administration of high doses, particularly intravenously, can
cause stimulation of β1-adrenoceptors resulting in tachycardia, which may limit the
dose. Lower doses are sometimes associated with β2-mediated vasodilatation, which
may reduce the blood pressure. It may also precipitate arrhythmias, especially in the
presence of hypokalaemia.

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Section III: Cardiovascular drugs
• Metabolic – Na+/K+ ATPase is stimulated and transports K+ into cells resulting in hypokalaemia. Blood sugar rises especially in diabetic patients and is exacerbated by concurrently administered steroids.
• Uterus – it relaxes the gravid uterus. A small amount crosses the placenta to reach the
fetus.
• Miscellaneous – a direct efect on skeletal muscle may produce tremor.

Kinetics
he absorption of salbutamol from the gut is incomplete and is subject to a signiicant
hepatic irst-pass metabolism. Following inhalation or intravenous administration, it
has a rapid onset of action. It is 10% protein-bound and has a half-life of 4–6 hours. It is
metabolized in the liver to the inactive 4-O-sulfate, which is excreted along with salbutamol in the urine.

Salmeterol
Salmeterol is a long-acting β2-agonist used in the treatment of nocturnal and exerciseinduced asthma. It should not be used during acute attacks due to a relatively slow
onset.
It has a long non-polar side chain, which binds to the β2-adrenoceptor giving it a long
duration of action (about 12 hours). It is 15 times more potent than salbutamol at the
β2-adrenoceptor, but four times less potent at the β1-adrenoceptor. It prevents the release
of histamine, leukotrienes and prostaglandin D2 from mast cells, and also has additional
anti-inlammatory efects that difer from those induced by steroids.
Its efects are similar to those of salbutamol.

Ritodrine
Ritodrine is a β2-agonist that is used to treat premature labour. Tachycardia (β1 efect) is
often seen during treatment. It crosses the placenta and may result in fetal tachycardia.
Ritodrine has been associated with fatal maternal pulmonary oedema. It also
causes hypokalaemia, hyperglycaemia and, at higher levels, vomiting, restlessness and

seizures.

Terbutaline
Terbutaline is a β2-agonist with some activity at β1-adrenoceptors. It is used in the treatment of asthma and uncomplicated preterm labour. It has a similar side-efect proile to
other drugs in its class.

Mixed (α and β)
Ephedrine
Ephedrine is found naturally in certain plants but is synthesized for medical use.
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13: Sympathomimetics

Presentation and uses
Ephedrine is formulated as tablets, an elixir, nasal drops and as a solution for injection
containing 30 mg/ml. It can exist as four isomers but only the L -isomer is active. It is used
intravenously to treat hypotension associated with regional anaesthesia. In the obstetric
setting this is now known to result in a poorer cord gas pH when compared to purer α
agonists, but its widespread use persists due to the potential for the α agonists to cause a
signiicant maternal hypertension. It is also used to treat bronchospasm, nocturnal enuresis and narcolepsy.

Mechanism of action
Ephedrine has both direct and indirect sympathomimetic actions. It also inhibits the
actions of MAO on noradrenaline.
Owing to its indirect actions it is prone to tachyphylaxis as noradrenaline stores in sympathetic nerves become depleted.

Effects
• Cardiovascular – it increases the cardiac output, heart rate, blood pressure, coronary
blood low and myocardial oxygen consumption. Its use may precipitate arrhythmias.
• Respiratory – it is a respiratory stimulant and causes bronchodilation.
• Renal – renal blood low is decreased and the glomerular iltration rate falls.
• Interactions – it should be used with extreme caution in those patients taking MAOI.

Kinetics
Ephedrine is well absorbed orally, intramuscularly and subcutaneously. Unlike adrenaline it is not metabolized by MAO or COMT and, therefore, has a longer duration of
action and an elimination half-life of 4 hours. Some is metabolized in the liver but 65% is
excreted unchanged in the urine.

Metaraminol
Metaraminol is a synthetic amine with both direct and indirect sympathomimetic
actions. It acts mainly via α1-adrenoceptors but also retains some β-adrenoceptor
activity.

Presentation and uses
Metaraminol is presented as a clear solution containing 10 mg/ml. It is used to correct
hypotension associated with spinal or epidural anaesthesia. An intravenous bolus of
0.5–2 mg is usually suicient.

Effects
• Cardiovascular – its main actions are to increase systemic vascular resistance, which
leads to an increased blood pressure. Despite its activity at β-adrenoceptors the cardiac
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Section III: Cardiovascular drugs
Theophylline
O

H
N

N
O

N

N
CH3

Enoximone
O
CH3

S

CH3

C
N

N
O

Milrinone
N
CN

CH3

N

O

H

Figure 13.5 Structure of some phosphodiesterase inhibitors.

output often drops in the face of the raised systemic vascular resistance. Coronary
artery low increases by an indirect mechanism. Pulmonary vascular resistance is also
increased leading to raised pulmonary artery pressure.

Other inotropic agents
Non-selective phosphodiesterase inhibitors
Aminophylline
Aminophylline is a methylxanthine derivative. It is a complex of 80% theophylline
and 20% ethylenediamine (which has no therapeutic efect but improves solubility)
(Figure 13.5).

Presentation and uses
Aminophylline is available as tablets and as a solution for injection containing 25 mg/ml.
Oral preparations are often formulated as slow release due to its half-life of about 6 hours.
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13: Sympathomimetics
It is used in the treatment of asthma where the dose ranges from 450 to 1250 mg daily.
When given intravenously during acute severe asthma a loading dose of 6 mg/kg over 20
minutes is given, followed by an infusion of 0.5 mg/kg/h. It may also be used to reduce
the frequency of episodes of central apnoea in premature neonates. It is very occasionally
used in the treatment of heart failure.

Mechanism of action
Aminophylline is a non-selective inhibitor of all ive phosphodiesterase isoenzymes,
which hydrolyse cAMP and possibly cGMP, thereby increasing their intracellular levels. It may also directly release noradrenaline from sympathetic neurones and demonstrate synergy with catecholamines, which act via adrenoceptors to increase intracellular
cAMP. In addition it interferes with the translocation of Ca2+ into smooth muscle, inhibits
the degranulation of mast cells by blocking their adenosine receptors and potentiates
prostaglandin synthetase activity.

Effects
• Respiratory – aminophylline causes bronchodilation, improves the contractility of
the diaphragm and increases the sensitivity of the respiratory centre to carbon dioxide. It works well in combination with β2-agonists due to the diferent pathway used to
increase cAMP.
• Cardiovascular – it has mild positive inotropic and chronotropic efects and causes
some coronary and peripheral vasodilatation. It lowers the threshold for arrhythmias
(particularly ventricular) especially in the presence of halothane.
• Central nervous system – the alkyl group at the 1-position (also present in cafeine) is
responsible for its central nervous system stimulation, resulting in a reduced seizure
threshold.
• Renal – the alkyl group at the 1-position is also responsible for its weak diuretic efects.
Inhibition of tubular Na+ reabsorption leads to a natriuresis and may precipitate

hypokalaemia.
• Interactions – co-administration of drugs that inhibit hepatic cytochrome P450 (cimetidine, erythromycin, ciproloxacin and oral contraceptives) tend to delay the elimination of aminophylline and a reduction in dose is recommended. he use of certain
selective serotonin re-uptake inhibitors (luvoxamine) should be avoided with aminophylline as levels of the latter may rise sharply. Drugs that induce hepatic cytochrome
P450 (phenytoin, carbamazepine, barbiturates and rifampicin) increase aminophylline clearance and the dose may need to be increased.

Kinetics
Aminophylline is well absorbed from the gut with a high oral bioavailability (>90%).
About 50% is plasma protein-bound. It is metabolized in the liver by cytochrome P450
to inactive metabolites and interacts with the metabolism of other drugs undergoing

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Section III: Cardiovascular drugs
metabolism by a similar route. Owing to its low hepatic extraction ratio its metabolism
is independent of liver blood low. Approximately 10% is excreted unchanged in the
urine. he efective therapeutic plasma concentration is 10–20 µg/ml. Cigarette smoking
increases the clearance of aminophylline.

Toxicity
Above 35 µg/ml, hepatic enzymes become saturated and its kinetics change from irstto zero-order resulting in toxicity. Cardiac toxicity manifests itself as tachyarrhythmias
including ventricular ibrillation. Central nervous system toxicity includes tremor,
insomnia and seizures (especially following rapid intravenous administration). Nausea
and vomiting are also a feature, as is rhabdomyolysis.

Selective phosphodiesterase inhibitors
Enoximone

he imidazolone derivative enoximone is a selective phosphodiesterase III inhibitor.

Presentation and uses
Enoximone is available as a yellow liquid (pH 12) for intravenous use containing 5 mg/
ml. It is supplied in propyl glycol and ethanol and should be stored between 5°C and 8°C.
It is used to treat congestive heart failure and low cardiac output states associated with
cardiac surgery. It should be diluted with an equal volume of water or 0.9% saline in plastic syringes (crystal formation is seen when mixed in glass syringes) and administered as
an infusion of 5–20 µg/kg/min, which may be preceded by a loading dose of 0.5 mg/kg,
and can be repeated up to a maximum of 3 mg/kg. Unlike catecholamines it may take up
to 30 minutes to act.

Mechanism of action
Enoximone works by preventing the degradation of cAMP and possibly cGMP in cardiac and vascular smooth muscle. By efectively increasing cAMP within the myocardium, it increases the slow Ca2+ inward current during the cardiac action potential. his
produces an increase in Ca2+ release from intracellular stores and an increase in the
Ca2+ concentration in the vicinity of the contractile proteins, and hence to a positive
inotropic efect. By interfering with Ca2+ lux into vascular smooth muscle it causes
vasodilatation.

Effects
• Cardiovascular – enoximone has been termed an ‘inodilator’ due to its positive inotropic and vasodilator efects on the heart and vascular system. In patients with heart
failure the cardiac output increases by about 30% while end diastolic illing pressures

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13: Sympathomimetics
decrease by about 35%. he myocardial oxygen extraction ratio remains unchanged by

virtue of a reduced ventricular wall tension and improved coronary artery perfusion.
he blood pressure may remain unchanged or fall, the heart rate remains unchanged
or rises slightly and arrhythmias occur only rarely. It shortens atrial, AV node and ventricular refractoriness. When used in patients with ischaemic heart disease, a reduction
in coronary perfusion pressure and a rise in heart rate may outweigh the beneits of
improved myocardial blood low so that further ischaemia ensues.
• Miscellaneous – agranulocytosis has been reported.

Kinetics
While enoximone is well absorbed from the gut an extensive irst-pass metabolism
renders it useless when given orally. About 70% is plasma protein-bound and metabolism occurs in the liver to a renally excreted active sulfoxide metabolite with 10% of
the activity of enoximone and a terminal half-life of 7.5 hours. Only small amounts are
excreted unchanged in the urine and by infusion enoximone has a terminal half-life of
4.5 hours. It has a wide therapeutic ratio and the risks of toxicity are low. he dose should
be reduced in renal failure.

Milrinone
Milrinone is a bipyridine derivative and a selective phosphodiesterase III inhibitor with
similar efects to enoximone. However, it has been associated with an increased mortality
rate when administered orally to patients with severe heart failure.

Preparation and uses
Milrinone is formulated as a yellow solution containing 1 mg/ml and may be stored at
room temperature. It should be diluted before administration and should only be used
intravenously for the short-term management of cardiac failure.

Kinetics
Approximately 70% is plasma protein-bound. It has an elimination half-life of 1–2.5
hours and is 80% excreted in the urine unchanged. he dose should be reduced in renal
failure.

Glucagon
Within the pancreas, α-cells secrete the polypeptide glucagon. he activation of glucagon receptors, via G-protein mediated mechanisms, stimulates adenylate cyclase and
increases intracellular cAMP. It has only a limited role in cardiac failure, occasionally
being used in the treatment of β-blocker overdose by an initial bolus of 10 mg followed
by infusion of up to 5 mg/hour. Hyperglycaemia and hyperkalaemia may complicate
its use.

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Section III: Cardiovascular drugs

Ca2+
While intravenously administered Ca2+ salts often improve blood pressure for a few minutes, their use should be restricted to circulatory collapse due to hyperkalaemia and Ca2+
channel antagonist overdose.

T3
hyroxine (T4) and triiodothyronine (T3) have positive inotropic and chronotropic efects
via intracellular mechanisms. hey are only used to treat hypothyroidism and are discussed in more detail in Chapter 26.

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14

Adrenoceptor antagonists

• α-Adrenoceptor antagonists
• β-Adrenoceptor antagonists
• Combined α- and β-adrenoceptor antagonists

α-Adrenoceptor antagonists
α-Adrenoceptor antagonists (α-blockers) prevent the actions of sympathomimetic
agents on α-adrenoceptors. Certain α-blockers (phentolamine, phenoxybenzamine) are
non-speciic and inhibit both α1- and α2-receptors, whereas others selectively inhibit α1receptors (prazosin) or α2-receptors (yohimbine). he actions of speciic α-adrenoceptor
stimulation are shown in Table 14.1.

Non-selective α-blockade
Phentolamine
Phentolamine (an imidazolone) is a competitive non-selective α-blocker. Its ainity for
α1-adrenoceptors is three times that for α2-adrenoceptors.

Presentation
It is presented as 10 mg phentolamine mesylate in 1 ml clear pale-yellow solution. he
intravenous dose is 1–5 mg and should be titrated to efect. he onset of action is 1–2
minutes and its duration of action is 5–20 minutes.

Uses
Phentolamine is used in the treatment of hypertensive crises due to excessive sympathomimetics, MAOI reactions with tyramine and phaeochromocytoma, especially during tumour manipulation. It has a role in the assessment of sympathetically mediated
chronic pain and has previously been used to treat pulmonary hypertension. Injection
into the corpus cavernosum has been used to treat impotence due to erectile failure.

Effects
• Cardiovascular – α1-blockade results in vasodilatation and hypotension while α2blockade facilitates noradrenaline release leading to tachycardia and a raised cardiac

output. Pulmonary artery pressure is also reduced. Vasodilatation of vessels in the
nasal mucosa leads to marked nasal congestion.
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Section III: Cardiovascular drugs
Table 14.1 Actions of specific α-adrenoceptor stimulation.
Receptor type

Postsynaptic
α1-Receptors

α2-Receptors

Presynaptic
α2-Receptors

Action

vasoconstriction
mydriasis
contraction of bladder sphincter
platelet aggregation
hyperpolarization of some CNS
neurones
inhibit noradrenaline release

• Respiratory – the presence of sulites in phentolamine ampoules may lead to hypersensitivity reactions, which are manifest as acute bronchospasm in susceptible
asthmatics.
• Gut – phentolamine increases secretions and motility of the gastrointestinal tract.
• Metabolic – it may precipitate hypoglycaemia secondary to increased insulin
secretion.

Kinetics
he oral route is rarely used and has a bioavailability of 20%. It is 50% plasma proteinbound and extensively metabolized, leaving about 10% to be excreted unchanged in the
urine. Its elimination half-life is 20 minutes.

Phenoxybenzamine
Phenoxybenzamine is a long-acting non-selective α-blocker. It has a high ainity for α1adrenoceptors.

Presentation
It is presented as capsules containing 10 mg and as a clear, faintly straw-coloured solution for injection containing 100 mg/2 ml phenoxybenzamine hydrochloride with ethyl
alcohol, hydrochloric acid and propylene glycol.

Uses
Phenoxybenzamine is used in the pre-operative management of phaeochromocytoma
(to allow expansion of the intravascular compartment), peri-operative management of
some neonates undergoing cardiac surgery, hypertensive crises and occasionally as an
adjunct to the treatment of severe shock. he oral dose starts at 10 mg and is increased
daily until hypertension is controlled, the usual dose is 1–2 mg.kg−1.day−1. Intravenous
administration should be via a central cannula and the usual dose is 1 mg.kg−1.day−1 given

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14: Adrenoceptor antagonists
as a slow infusion in at least 200 ml 0.9% saline. β-blockade may be required to limit relex
tachycardia.

Mechanism of action
Its efects are mediated by a reactive intermediate that forms a covalent bond to the
α-adrenoceptor resulting in irreversible blockade. In addition to receptor blockade, phenoxybenzamine inhibits neuronal and extra-neuronal uptake of catecholamines.

Effects
• Cardiovascular – hypotension, which may be orthostatic, and relex tachycardia are
characteristic. Overdose should be treated with noradrenaline. Adrenaline will lead to
unopposed β efects thereby compounding the hypotension and tachycardia. here is
an increase in cardiac output and blood low to skin, viscera and nasal mucosa leading
to nasal congestion.
• Central nervous system – it usually causes marked sedation although convulsions have
been reported after rapid intravenous infusion. Meiosis is also seen.
• Miscellaneous – impotence, contact dermatitis.

Kinetics
Phenoxybenzamine is incompletely and variably absorbed from the gut (oral bioavailability about 25%). Its maximum efect is seen at 1 hour following an intravenous dose.
he plasma half-life is about 24 hours and its efects may persist for 3 days while new
α-adrenoceptors are synthesized. It is metabolized in the liver and excreted in urine
and bile.

Selective α1-blockade
Prazosin
Prazosin (a quinazoline derivative) is a highly selective α1-adrenoceptor antagonist.

Presentation and uses

Prazosin is available as 0.5–2 mg tablets. It is used in the treatment of essential hypertension, congestive heart failure, Raynaud’s syndrome and benign prostatic hypertrophy.
he initial dose is 0.5 mg tds, which may be increased to 20 mg per day.

Effects
• Cardiovascular – prazosin produces vasodilatation of arteries and veins and a reduction of systemic vascular resistance with little or no relex tachycardia. Diastolic pressures fall the most. Severe postural hypotension and syncope may follow the irst dose.
Cardiac output may increase in those with heart failure secondary to reduced illing
pressures.

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Section III: Cardiovascular drugs
• Urinary – it relaxes the bladder trigone and sphincter muscle thereby improving urine
low in those with benign prostatic hypertrophy. Impotence and priapism have been
reported.
• Central nervous system – fatigue, headache, vertigo and nausea all decrease with
continued use.
• Miscellaneous – it may produce a false-positive when screening urine for metabolites of
noradrenaline (VMA and MHPG seen in phaeochromocytoma).

Kinetics
Plasma levels peak about 90 minutes following an oral dose with a variable oral bioavailability of 50–80%. It is highly protein-bound, mainly to albumin, and is extensively
metabolized in the liver by demethylation and conjugation. Some of the metabolites are
active. It has a plasma half-life of 3 hours. It may be used safely in patients with renal
impairment as it is largely excreted in the bile.

Selective α2-blockade

Yohimbine
he principal alkaloid of the bark of the yohimbe tree is formulated as the hydrochloride
and has been used in the treatment of impotence. It has a variable efect on the cardiovascular system, resulting in a raised heart rate and blood pressure, but may precipitate
orthostatic hypotension. In vitro it blocks the hypotensive responses of clonidine. It has
an antidiuretic efect and can cause anxiety and manic reactions. It is contraindicated in
renal or hepatic disease.

β-Adrenoceptor antagonists
β-Adrenoceptor antagonists (β-blockers) are widely used in the treatment of hypertension, angina and peri-myocardial infarction.
hey are also used in patients with phaeochromocytoma (preventing the relex
tachycardia associated with α-blockade), hyperthyroidism (propranolol), hypertrophic
obstructive cardiomyopathy (to control infundibular spasm), anxiety associated with
high levels of catecholamines, topically in glaucoma, in the prophylaxis of migraine and
to suppress the response to laryngoscopy and at extubation (esmolol).
hey are all competitive antagonists with varying degrees of receptor selectivity. In
addition some have intrinsic sympathomimetic activity (i.e. are partial agonists), whereas
others demonstrate membrane stabilizing activity. hese three features form the basis
of their difering pharmacological proiles (Table 14.2). Prolonged administration may
result in an increase in the number of β-adrenoceptors.

Receptor selectivity
In suitable patients, the useful efects of β-blockers are mediated via antagonism of
β1-adrenoceptors, while antagonism of β2-adrenoceptors results in unwanted efects.
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14: Adrenoceptor antagonists

Table 14.2 Comparison between receptor selectivity, intrinsic sympathomimetic activity and
membrane stabilizing activity of various β-blockers.

Acebutolol
Atenolol
Esmolol
Metoprolol
Pindolol
Propranolol
Sotalol
Timolol
Labetalol

β1-receptor selectivitycardioselectivity

Intrinsic sympathomimetic
activity

Membrane stabilizing
activity

+
++
++
++
−
−
−
−
−

+
−
−
−
++
−
−
+
±

+
−
−
+
+
++
−
+
+

Atenolol, esmolol and metoprolol demonstrate β1-adrenoceptor selectivity (cardioselectivity) although when given in high dose β2-antagonism may also be seen. All β-blockers
should be used with extreme caution in patients with poor ventricular function as they
may precipitate serious cardiac failure.

Intrinsic sympathomimetic activity – partial agonist activity
Partial agonists are drugs that are unable to elicit the same maximum response as a full
agonist despite adequate receptor ainity. In theory, β-blockers with partial agonist activity will produce sympathomimetic efects when circulating levels of catecholamines are
low, while producing antagonist efects when sympathetic tone is high. In patients with
mild cardiac failure they should be less likely to induce bradycardia and heart failure.

However, they should not be used in those with more severe heart failure as β-blockade
will further reduce cardiac output.

Membrane stabilizing activity
hese efects are probably of little clinical signiicance as the doses required to elicit them
are higher than those seen in vivo.

Effects
• Cardiac – β-blockers have negative inotropic and chronotropic properties on cardiac
muscle; sino-atrial (SA) node automaticity is decreased and atrioventricular (AV)
node conduction time is prolonged leading to a bradycardia, while contractility is also
reduced. he bradycardia lengthens the coronary artery perfusion time (during diastole) thereby increasing oxygen supply while reduced contractility diminishes oxygen
demand. hese efects are more important than those that tend to compromise the supply/demand equation, that is, prolonged systolic ejection time, dilation of the ventricles
and increased coronary vascular resistance (due to antagonism of the vasodilatory β2
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